Small Mechanical Strains Selectively Suppress Matrix Metalloproteinase-1 Expression by Human Vascular Smooth Muscle Cells*
- From the Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115
Abstract
Mechanical forces and biochemical stimuli may interact to regulate cellular responses. In this study, we tested the hypothesis that very small mechanical strains interact with growth factors in the regulation of matrix metalloproteinase (MMP)-1. Human vascular smooth muscle cells (VSMCs) were cultured on a precoated silicone membrane in a device that imposes a highly uniform biaxial strain. VSMCs cultured on fibronectin were treated with cyclic 1-Hz strains of 0, 1, or 4%, and MMPs were assayed by Western analysis or gelatin zymography. Small strains did not induce MMP-1 in VSMCs, but strain was a potent inhibitor of platelet-derived growth factor (PDGF)- or tumor necrosis factor-α-induced synthesis of MMP-1. In contrast, MMP-2 and TIMP-2 levels were not changed by PDGF and/or mechanical strain. VSMCs strained on the 120-kDa chymotryptic fragment of fibronectin or RGD peptides suppressed PDGF-induced expression of MMP-1, indicating that this effect is not mediated by the heparin-binding domain or connecting segment-1 of fibronectin. Northern analysis of ets-1, a transcriptional activator of MMP-1 expression, showed that strain down-regulated ets-1expression, whereas c-fos expression was augmented. Thus, small deformations can selectively suppress MMP-1 synthesis by VSMCs, demonstrating the exquisite sensitivity of the cell to mechanical stimuli.
Footnotes
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↵* This work was supported in part by a grant-in-aid from the American Heart Association and by Grants HL-48743 and HL-54759 from NHLBI, National Institutes of Health.
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↵‡ Supported in part by a grant from the Korea Science and Engineering Foundation.
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↵§ To whom correspondence should be addressed: Cardiovascular Div., Brigham and Women’s Hospital, 75 Francis St., Boston, MA 02115. Tel.: 617-732-7146; Fax: 617-277-4981; E-mail:RTLEE{at}BICS.BWH.HARVARD.EDU.
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↵1 The abbreviations used are: VSMCs, vascular smooth muscle cells; PDGF, platelet-derived growth factor; MMP, matrix metalloproteinase; IL-1, interleukin-1; TNF-α, tumor necrosis factor-α; FN, fibronectin; DMEM, Dulbecco’s modified Eagle’s medium; FCS, fetal calf serum.
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↵2 J.-H. Yang, W. H. Briggs, P. Libby, and R. T. Lee, unpublished observations.
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- Received July 25, 1997.
- Revision received December 18, 1997.
- The American Society for Biochemistry and Molecular Biology, Inc.
